Microglia are the resident macrophages of the brain and retina. They become activated in diseases such as diabetes and retinal degeneration where cells die, causing microglia to phagocytose cellular debris. Activation of retinal microglia occurs in a mouse model of ischemia/reperfusion injury (I/R), as occurs in inflammatory diseases of the eye, including glaucoma, age related macular degeneration (AMD), diabetic retinopathy and branch vein occlusion. Retinal vascular occlusion, be it by high intra-ocular pressure in the I/R model or thrombus in BVO, causes a decrease in blood flow within the eye resulting in retinal ischemia. This causes death of neurons initiating further activation of microglia.
Exudative (wet form) AMD is characterized by serous or hemorrhagic separation of the retinal pigment epithelium or neurosensory layer. Patients may develop choroidal neovascularization (CNV), which is manifested as fluid accumulation, hemorrhage, and/or lipid exudation.
The earliest stage of diabetic retinopathy (DR) is characterized by retinal vascular abnormalities including microaneurysms (saccular out-pouchings from the capillary wall), intraretinal hemorrhages, and cotton-wool spots (nerve fiber layer infarctions). As the disease progresses, the gradual closure of retinal vessels results in retinal ischemia, giving rise to signs including venous abnormalities (beading, loops), intraretinal microvascular abnormalities, and increasing retinal hemorrhage and exudation. Non-proliferative diabetic retinopathy is graded as mild, moderate, severe, and very severe according to the presence and extent of the above lesions.
The more advanced stage of DR involves the formation of new blood vessels, induced by the retinal ischemia, which spreads out either from the disc (neovascularization of the disc, NVD) or from elsewhere in the retina (neovascularization elsewhere, NVE). New vessels extending into the vitreous can cause vitreous hemorrhage, and tractional retinal detachments associated with accompanying contractile fibrous tissue (FIG. 1).
Dendrimers are a group of nanostructured polymers that have the potential to deliver drugs and small molecule therapies because of their large number of functional groups, to intracellular domains. Kannan et al has shown the therapeutic utility of a dendrimer-based therapies in treating a rabbit model cerebral palsy (CP). This rabbit model replicates the neuro-inflammation seen in the adult brain during CP.
To date, the only treatment conclusively demonstrated to be of long term benefit for DR is focal laser photocoagulation.
The standard treatment for patients with AMD is intravitreal injections of anti-VEGF into the eye, and there have been studies that have shown that anti-VEGF therapy may be useful in diabetic macular edema (DME). However, systemic delivery would have many advantages beyond current treatments as there are at present no systemic treatments available for ischemic retinopathies or AMD. These advantages include less frequent injections due to retention in microglia and ability to delivery systemically, avoiding frequent intraocular injections as in current anti-VEGF therapies, or of drugs or drug releasing implants from erobable or non-erodable sustained release devices.
Currently, there are no targeted therapies for AMD or DR. Targeting the activated microglia/macrophages from systemic administration can increase efficacy of the drugs and reduce side effects.